1. Synthesis of Branched Trehalose Glycolipids and Their Mincle Agonist Activity
- Author
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Sho Yamasaki, Naoya Nishimura, Ashna A. Khan, Mattie S. M. Timmer, Bridget L. Stocker, and Jessie H. Bird
- Subjects
0301 basic medicine ,Agonist ,biology ,medicine.drug_class ,Organic Chemistry ,Trehalose ,Lectin ,NFAT ,Chemistry Techniques, Synthetic ,Green fluorescent protein ,Trehalose dimycolate ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Glycolipid ,Solubility ,chemistry ,Biochemistry ,Cell culture ,biology.protein ,medicine ,Lectins, C-Type ,Glycolipids - Abstract
The macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor that recognizes trehalose dimycolate (TDM), and trehalose dibehenate (TDB) and related trehalose diesters, and thus represents a promising target for the development of vaccine adjuvants based on the trehalose glycolipid scaffold. To this end, we report on the synthesis of a series of long-chain α-branched, β-modified trehalose monoesters and diesters to explore how glycolipid structure affects signaling through Mincle. Key steps in our synthetic strategy include a Frater-Seebach α-alkylation to install the C20 aliphatic lipid on a malic acid derivative, and the formation of a β,γ-epoxide as an intermediate from which modifications to the β-position of the lipid can be made. Biological evaluation of the derivatives using nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cell lines expressing mMincle or hMincle revealed that the hMincle agonist activity of all diesters was superior to that of...
- Published
- 2018